Medical cost of acute diarrhea in children in ambulatory care

Objective The aim of this study was to estimate the direct medical cost per episode and the annual cost for acute diarrhea (AD) in children under five years of age in Ambulatory Care Centers of the Ministry of Public Health (MOPH) of Ecuador. Methods A cost of illness study with a provider perspective was carried out through a micro-costing of health resources and valuated in international dollars. Medical consultations and laboratory tests were valued using the tariff framework of services for the National Health System and for the prescribed medications, a reported cost registry of pharmacy purchases made in the year of study was used. Results A total of 332 electronic health records of children under five years of age were included in the analysis. Laboratory tests were performed on 37.95% (126/332), medications were prescribed to 93.67% (311/332) of the children, and antimicrobials were prescribed to 37.35% (124/332) of the children, representing an antibiotic prescription rate of 26.51% (88/332) and an antiparasitic prescription rate of 10.84% (36/332). The mean cost of the MOPH per child per episode of AD was US$45.24 (2019 dollars) (95% CI:43.71 to 46.76). Conclusion The total estimated cost of AD in children under five years of age for the MOPH in 2019 was about US$6,645,167.88 million (2019 dollars) (95% CI: 6,420,430.77 to 6,868,436.12). A high proportion of the direct medical cost of AD in children under five years of age in outpatient settings is due to unnecessary laboratory tests.

resources used for a given disease and estimating the monetary expenditure. Advanced statistical tests are not necessary. "Other comments: The article focuses on treatment cost which is divided into two types, 1. Medication cost and 2. Lab test cost. On the other hand the article describes number of units dispensed from the facilities. So these two parameters should be clearly separated by headings and discussed accordingly in separate results heading." Suggestion accepted. Results were better discussed following the recommendation but meeting PLOS ONE's style requirements Reviewer #2: "Authors should be more clear on the methodology and presentation of results in approach that can be understood by a layman. The comments provided in the attached pdf documents should be addressed clearly and correctly." Suggestion accepted. This manuscript version has been corrected and rewritten to facilitate comprehension. All comments provided were properly addressed. 1.A definition of international dollar has been added. Lines 130-131. 2. Table 1 now includes information on comorbidities found in the sample. Line 152 3. Table 3 was reworked to improve comprehension. Line 176 4.US$ is used in the manuscript as the standard unit. "This part is not clear and confusing. The prevalence rate is not the same as the sample size. I disagree that you can extrapolate the data on national prevalence to estimate annual cost. The annual cost should stay within your sample size. This is because health cost will vary by location. So, you can not assume the cost in your location is the same as elsewhere." Cost-of-illness studies can be described as prevalence-based or incidence-based approaches, depending on how the epidemiological data are used. Prevalence-based studies can use this procedure to extrapolate cost and resource data over a period of time (1,2). This is called a prevalence approach. We partially agree with the reviewer, as this type of estimation may have some limitations; however, this is discussed in lines 260-655. For this reason, it is advisable to perform a sensitivity analysis (lines 266-276). The term sensitivity analysis is not appropriate here. The information provided here can be included in the discussion but not discussed as sensitivity analysis" Suggestion accepted. We discussed this analysis in the proper section. Lines 265-274.
"add " to the best of our knowledge"" "Remove the word reliable as there is no way your audience can confirm that adjective. It is ok to write that you provided data on resources used but you don't need to stress the reliability. The reliability of resources may be difficult to measure in this context." Suggestions accepted. Lines 231-233 "If you say numerous studies, you should cite references backing that statement." Suggestion accepted. Lines 246-247 "Rather say the result may not be generalized since it is a limitation and not that it can be generalized." Suggestion accepted. We have rephrased the sentence to improve comprehension. Lines 291-293.

Introduction 43
Diarrheal disease is one of the leading causes of death in children in developing countries [1]. 44 Acute diarrhea (AD) is defined as the passage of three or more loose or liquid stools per day [2]. It 45 primarily occurs in children during the first five years after birth, and particularly in the second 46 half-year and in little children [3]. It is estimated that 2.5 billion cases of diarrheal disease occur 47 each year in children under five years of age, and an average of more than 1,400 children die each 48 day [4]. Evidence shows that AD is common in places with poor access to health care, safe water 49 and sanitation, which is often observed in low and middle-income countries [5]. 50 The most common cause of AD is gastrointestinal infections caused by viruses, bacteria and 51 occasionally parasite. Rotavirus is responsible for 60-70% of all diarrheal diseases; however, E. Unnecessary use of resources in the treatment of AD leads to inefficient use of scarce healthcare 68 resources. It is estimated that a significant proportion of medical tests and drug prescriptions is 69 unnecessary around the world; this is of particular concern because of the potential financial effect 70 of excessive resource utilization on healthcare systems [12]. To date, no research has attempted to 71 estimate this cost burden on Ecuador's healthcare system, even when AD is a leading cause of   Table S1. We considered an acute diarrhea diagnosis to be any diagnosis 104 The following formula was applied to calculate the sample for a finite universe: n = N*Z 2 *p*q / 110 where N is the population size, Z is the confidence level (95%), p is the probability of success, or 112 expected proportion (50%), q is the probability of failure (50%), and d is precision (5% of 113 maximum admissible error in terms of proportion). The subsequently studied sample comprised 114 332 Electronic Health Records (EHR). 115

116
Perspective 117 A provider perspective was used, which included resources provided by the MOPH during the 118 period between the initial consultation and resolution of the illness up to a maximum of five weeks. 119 This included medical care, laboratory tests, and medication as primary resources. 120

Data source 121
The data source for the resources used and data collect in this study was the Electronic Health 122 Records (EHR) of the patients from 21 health centers of the Ministry of Public Health in the District 123 17D03 in Ecuador during 2019 with AD as a primary diagnosis. This district has been using the 124 EHR since 2010. Physicians enter information directly into the EHR on a computer during the 125 outpatient appointment. Information was manually extracted from the EHR by two reviewers. The 126 tests ordered and medication administered were verified against laboratory and pharmacy records. 127 illness study. The general characteristics of our sample are described in Table 1 In the same of children, the male gender was more frequent with 57.53% (191/332) and the mean 152 age was 1.29 years. Most of the registered children, 89.75% (198/332), had no comorbidities; 153 chronic malnutrition and anemia were the most frequent comorbidities reported, with 3.92% 154 (13/332) and 3.31% (11/332) respectively. Of the total number of AD consultations, general 155 practitioner consultations were more frequent with 45.78% (152/332) followed by pediatrician 156 consultations with 25.30% (84/332). 157

Valuation of resources
A total of 91 healthcare professionals treated all the cases coded as AD, with females being the 158 most frequent (64.84% vs. 35.16%) and the mean age of the professionals was 40.5. Two types of 159 health care professionals were included: general physicians (Rural Doctor and General 160 Practitioner) and specialists (Family Medicine Physician and Pediatrician), general physicians were 161 the most frequent health professionals (68.12% vs. 31.88%). 162 The ICD-10 diagnostic code most frequently assigned by physicians was A09 (Other gastroenteritis 163 and colitis of infectious and unspecified origin) in 98.19% (326/332) of the cases ( Table 2). 164 The total resource use in the sample by item is shown in Table 3. A total of 1546 resources were 170 used in 332 children. All children had one primary care contact, and the re-consultation rate was 171 9.94% (33/332); out of these, just one child needed two re-consultations. 172

228
To the best of our knowledge, this is the first study to measure AD management costs in children 229 under five years of age in Ecuador. Our data provide statistics on resource use and costs from a 230 payer perspective. The cost was estimated from medical records with diagnoses coded according 231 to ICD-10, applying a micro-cost methodology by involving the direct identification and valuation 232 of the resources consumed treating each patient, which improves the accuracy of cost estimation 233 Medical appointments represent 23.67% of the resources used per AD episode. All children had at 235 least an initial consultation and the rate of re-consultation was almost 10%, which is less than that 236 reported in the literature [21]. Laboratory tests were ordered in almost 38% of the children, 237 accounting for around the 20% of the resources used.  Nevertheless, the proportion of laboratory and medication costs were higher in Rheingans' study, 251 between 50% and 80%, compared to our data, which was less than 20%. Alternatively, a systematic  The Integrated Management of Childhood Illness (IMCI) strategy was designed in 1996 by the 281 the quality of care for children in primary care services and was adopted by Ecuador [40]. 283 According to this strategy, in patients under five years of age with AD, it is not necessary to request 284 laboratory tests, and the use of antibiotics is justified in few circumstances; therefore, our findings 285 show that there may be an overuse of these resources and lack of adherence to IMCI 286 recommendations, a situation that has been reported in other studies [41,42]. However, the 287 evaluation of the strategy and its implementation is beyond our research objectives.     Diarrheal disease is one of the leading causes of death in children in developing countries [1]. 44 Acute diarrhea (AD) is defined as the passage of three or more loose or liquid stools per day [2]. It 45 primarily occurs in children during the first five years after birth, and particularly in the second 46 half-year and in little children [3]. It is estimated that 2.5 billion cases of diarrheal disease occur 47 each year in children under five years of age, and an average of more than 1,400 children die each 48 day [4]. Evidence shows that AD is common in places with poor access to health care, safe water 49 and sanitation, which is often observed in low and middle-income countries [5]. 50 The most common cause of AD is gastrointestinal infections caused by viruses, bacteria and 51 occasionally parasite. Rotavirus is responsible for 60-70% of all diarrheal diseases; however, E. Unnecessary use of resources in the treatment of AD leads to inefficient use of scarce healthcare 68 resources. It is estimated that a significant proportion of medical tests and drug prescriptions is 69 unnecessary around the world; this is of particular concern because of the potential financial effect 70 of excessive resource utilization on healthcare systems [12]. To date, no research has attempted to 71 estimate this cost burden on Ecuador's healthcare system, even when AD is a leading cause of  Table S1. We considered an acute diarrhea diagnosis to be any diagnosis 104  In the same of children, the male gender was more frequent with 57.53% (191/332) and the mean 154 The ICD-10 diagnostic code most frequently assigned by physicians was A09 (Other gastroenteritis 165 and colitis of infectious and unspecified origin) in 98.19% (326/332) of the cases ( Table 2). 166 The total resource use in the sample by item is shown in Table 3. A total of 1546 resources were 172 used in 332 children. All children had one primary care contact, and the re-consultation rate was 173 9.94% (33/332); out of these, just one child needed two re-consultations.

230
To the best of our knowledge, this is the first study to measure AD management costs in children 231 under five years of age in Ecuador. Our data provide statistics on resource use and costs from a 232 payer perspective. The cost was estimated from medical records with diagnoses coded according 233 to ICD-10, applying a micro-cost methodology by involving the direct identification and valuation 234 of the resources consumed treating each patient, which improves the accuracy of cost estimation 235 [20]. 236 Medical appointments represent 23.67% of the resources used per AD episode. All children had at 237 least an initial consultation and the rate of re-consultation was almost 10%, which is less than that reported in the literature [21]. Laboratory tests were ordered in almost 38% of the children, 239 accounting for around the 20% of the resources used. Nevertheless, the proportion of laboratory and medication costs were higher in Rheingans' study, 253 between 50% and 80%, compared to our data, which was less than 20%. Alternatively, a systematic do not greatly affect the results as we found them to be relatively low cost. 274 Cost-of-illness studies can estimate cost based on epidemiological data, through incidence-based 275 or prevalence-based approaches [37]; the latter is useful for identifying points for cost containment, 276 as this approach provides information on each cost component [38,39]. 277 The total estimated cost of AD in children under five years of age for MOPH in 2019 was about 278 US$6,645,167.88 (2019 dollars) (95% CI: 6,420,430.77 to 6,868,436.12). If laboratory tests had 279 been minimized and antibiotic use cut by at least half, our annual cost estimate would have been 280 reduced by $1 million. Therefore, an intervention that promotes rational use of these resources 281 would be cost saving. 282 The Integrated Management of Childhood Illness (IMCI) strategy was designed in 1996 by the 283 World Health Organization (WHO) and the United Nations Children's Fund (UNICEF) to improve 284 the quality of care for children in primary care services and was adopted by Ecuador [40]. 285 According to this strategy, in patients under five years of age with AD, it is not necessary to request 286 laboratory tests, and the use of antibiotics is justified in few circumstances; therefore, our findings 287 show that there may be an overuse of these resources and lack of adherence to IMCI 288 recommendations, a situation that has been reported in other studies [41,42]. However, the 289 evaluation of the strategy and its implementation is beyond our research objectives. 290 A limitation of this study is that it focuses only on the population subsidized by the MOPH; 291 although it covers most of the country's population[43], the results may not be generalizable to 292 other public health subsystems. Another limitation is the perspective used in the study; we did not 293 include patient time costs or other associated resource costs. This perspective is narrower and does 294 not include patients' out-of-pocket costs as they are not borne by payers; therefore, the cost of 295 illness may be underestimated. A strength of the study is that the AD cases were selected from the 296 medical records of different health centers, according to ICD-10, which allowed us to obtain data 297 according to their own diagnoses and thus determine the use of resources for such care. Moreover, 298 the study shows relevant data for decision-making stakeholders to consider cost containment 299 measures for the efficient use of medical resources. 300

301
A high proportion of the direct medical cost of AD in children under five years of age in outpatient 302 settings is due to the unnecessary use of laboratory tests. Factors that may influence the overuse of 303 this resource in primary care need to be explored. 304 I think it is good to provide a recommendation here to mitigate the observed concerns rather than just asking for more studies.